Diabetes is generally classified in two main groups. In type I diabetes, auto-immune destruction of beta cells within the islets of Langerhans leads to a marked defect in insulin production. In contrast, type II diabetes is characterized by insulin resistance in muscle, fat, and liver along with a relative impairment of insulin production in beta cells. Multiple genes contribute to susceptibility in both type I and type II diabetes, although in most cases their identities remain unknown.
Apoptosis is an active process of cellular self-destruction that is regulated by extrinsic and intrinsic signals occurring during normal development. It is well documented that apoptosis plays a key role in the plasticity of pancreatic endocrine beta cells. There is increasing evidence that in adult mammalians the beta-cell mass is submitted to dynamic changes to adapt insulin production for maintaining euglycemia in particular conditions, such as pregnancy and obesity. The control of beta cell mass depends on a subtle balance between cell proliferation, growth and cell death (apoptosis). A disruption of this balance may lead to impairment of glucose homeostasis. For example, it is noteworthy that glucose intolerance develops with aging when the replication rate of beta cell is reduced and that patients with non-insulin-dependent-diabetes mellitus have a 40-60% loss of beta cell mass as compared with nondiabetic subjects. It is generally agreed that, in insulino-resistant subjects, normoglycemia is maintained by compensatory hyperinsulinemia until the beta cells become unable to meet the increased demand for insulin, at which point Type II Diabetes breaks out.
Type II or noninsulin-dependent diabetes mellitus (NIDDM) is a polygenic disease and accounts for >90% of diabetes cases. This disease is characterized by resistance to insulin action on glucose uptake and impaired insulin action to inhibit hepatic glucose production.
Regulation of glucose metabolism by insulin is a key mechanism by which homeostasis is maintained in an animal. Insulin stimulates uptake of glucose from the blood into tissues, especially muscle and fat. This occurs via increased translocation of Glut4, the insulin-sensitive glucose transporter, from an intracellular vesicular compartment to the plasma membrane. Glut4 is the most important insulin-sensitive glucose transporter in these tissues. Insulin binds to its receptor in the plasma membrane, generating a series of signals that result in the translocation or movement of Glut4 transporter vesicles to the plasma membrane.
Liver X receptors (LXRs) are members of a nuclear receptor superfamily that induce ligand dependent transcriptional activation of target genes. They play important roles in cholesterol metabolism and homeostasis. Two LXR proteins (alpha and beta) are known to exist in mammals. LXRalpha expression is high in organs involved in lipid homeostasis such as intestin, brown and white adipose tissues whereas LXRbeta is more ubiquitous and enriched in tissues of neuronal and endocrine origin. Recently, LXRalpha and beta have been found expressed in pancreatic islets as well as alpha cells and beta cells (Efanov et al, Diabetes, 53(3), S75-78, 2004).
LXRalpha and LXRbeta are closely related and share 77% amino acid identity in both their DNA- and ligand-binding domains. The LXRs are also conserved between humans and other animals (e.g., rodents). Like other nuclear receptors, LXRs heterodimerize with retinoid X receptor (RXR) for function. LXRs are known to be activated by certain naturally occurring, oxidized derivatives of cholesterol, including 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol and 24,25(S)-epoxycholesterol.
LXRalpha and beta are regulators of hepatic genes involved in cholesterol and fatty acid metabolism (HMGCOA synthase/reductase, farnesyl diphosphate synthase, squalene synthase, SREBP1c, stearoyl CoA desaturase (SCD1 and 2), FAS), inhibits expression of gluconeogenic enzymes (PEPCK, fructose biphosphatase1, glucose 6 phosphatase), induce expression of transmembrane transporter (ABCA1, Glut1 and Glut4), inhibit expression of enzymes involved in glycolysis (6-phosphofructo-2-kinase) and induce pyruvate dehydrogenase kinase 4 (a negative regulator of glycolysis), decrease 11-betahydroxysteroid dehydrogenase type 1 (enzyme that reactivates inactive cortisone in active cortisol in humans). Leptin and UCP-1 have been identified as target genes of LXR (down regulation by LXR agonists). Moreover, LXRs have overlapping functions with PPARs in the negative control of the inflammatory response. LXRs inhibit the production of TNFα and IL-1β and the expression of inflammatory mediators such as COX2, iNOS, IL-6. LXR may play a key role in responses to inflammation, and because it has been shown to be important in lipid metabolism, LXR might be involved in obesity-induced inflammatory responses as well. (reviewed in Steffensen et al, Diabetes, 2004, 53(1), S36-42).
In db/db mice, T0901317, a LXR agonist described here-below, has shown to lower plasma glucose level (not in normal mice). This compound inhibits the expression of PEPCK to limit hepatic glucose output (Cao et al, J Biol Chem, 2003, 278, 1131-1136).
Culture of pancreatic islets or insulin-secreting MIN6 cells with T0901317 caused an increase in glucose-dependent insulin secretion and islet insulin content. The stimulatory effect of this compound on insulin secretion was observed only after >72 h of islet culture with T0901317. In MIN6 cells, Tularik increased protein expression of lipogenic enzymes, fatty acid synthase and acetyl-CoA carboxylase. LXR activation also produced an increase in glucokinase protein and pyruvate carboxylase (PC) activity levels. LXRs could control insulin secretion and biosynthesis via regulation of glucose and lipid metabolism in pancreatic beta cell (Efanov et al, Diabetes, 53(3), S75-78, 2004).
The pancreatic duodenal homeobox gene-1 (Pdx-1) is a master regulator of both pancreatic development and the differentiation of progenitor cells into the beta cell phenotype. Moreover, in the differentiated beta cell, Pdx1 is a glucose-responsive regulator of insulin gene expression and the function of Pdx1 in response to glucose is regulated by both its phosphorylation and nuclear translocation. During the later stages of islet development, the expression of Pdx-1 becomes mostly restricted to the mature beta cells of the endocrine pancreas. In the adult pancreas, subpopulations of somatostatin-producing and pancreatic polypeptide-producing cells also express Pdx-1, only a few glucagon-producing cells express it.
A defect in glucose sensing of the pancreatic beta cells has been observed in several animal models of type II diabetes and has been correlated with a reduced gene expression of the glucose transporter type 2 (Glut2). In a transgenic mouse model, expression of Glut2 antisense RNA in pancreatic beta-cells has been shown to be associated with an impaired glucose-induced insulin secretion and the development of diabetes. The glucose transporter type 2 (GLUT2) gene expression is selectively decreased in the beta-pancreatic cells of experimental models of diabetes and the murine GLUT2 promoter is controlled by PDX-1.